GWAS Meta-Analysis Supports Existence of Autoimmune Disease Clusters

December 24, 2009

NEW YORK (GenomeWeb News) – A new paper in PLoS Genetics today suggests the same genetic variants that increase an individual’s risk for one set of autoimmune diseases may actually make them less susceptible to others.

Researchers from Stanford University and collaborators at a California hospital and clinical center did a meta-analysis of genome-wide association studies on half a dozen autoimmune conditions, including type 1 diabetes and rheumatoid arthritis. They found a pattern in which specific diseases grouped together based on SNP data, with variants that increased the risk of some conditions protecting against others.

Based on these findings, the team suggests it may be useful to classify autoimmune diseases according to their shared genetic factors rather than considering them a single group.

“Maybe we should stop considering all autoimmune diseases in one lumped category,” senior author Atul Butte, a pediatric and bioinformatics researcher at Stanford University and director of the Lucile Packard Children’s Hospital’s Center for Pediatric Bioinformatics, said in a statement. “It looks as if there may be at least two different kinds.”

Although autoimmune diseases share some common disease mechanisms, Butte and his team noted, certain autoimmune diseases have more in common than others. For example, past research suggests that individuals with type 1 diabetes are at increased risk for autoimmune diseases such as autoimmune thyroid disease, multiple sclerosis, and celiac disease.

And, they added, at least one SNP has already been shown to have opposing effects in different autoimmune conditions: the G allele of that SNP, called rs2076530, is more common in individuals with type 1 diabetes or rheumatoid arthritis whereas the A allele is more common in those with systematic lupus erythematosus.

That led Butte and his colleagues to speculate about how genetic factors relate to autoimmune disease clusters. In the current paper, the team did a meta-analysis involving 573 SNPs assessed in several GWAS of six autoimmune diseases — type 1 diabetes, rheumatoid arthritis, Crohn’s disease, multiple sclerosis, autoimmune thyroid disease, and ankylosing spondylitis — and five non-autoimmune diseases.

By assessing alleles associated with each disease and the strength of these associations, the team came up with a so-called “genetic variation score” to evaluate ties between specific alleles and diseases across different genotyping platforms.

Of the nearly 600 SNPs evaluated, the team found nine SNPs for which one allele appears to increase an individual’s risk of multiple sclerosis and autoimmune thyroid disease but decrease his or her risk of rheumatoid arthritis and ankylosing spondylitis. The alternative alleles for these SNPs, meanwhile, have the opposite effect.

“What was surprising was our finding that at nine locations generally associated with autoimmunity risk, where a particular chemical unit conferred a heightened risk of certain autoimmune diseases, but reduced risk of getting certain others,” lead author Marina Sirota, a graduate student in Butte’s Stanford University lab, said in a statement.

Based on their analyses, the researchers suggest autoimmune diseases fall into at least two different groups: one containing rheumatoid arthritis and ankylosing spondylitis and another containing multiple sclerosis and autoimmune thyroid disease.

Meanwhile, they reported, type 1 diabetes resembled both of the groups to a certain extent, sharing characteristics with autoimmune thyroid disease but not multiple sclerosis. Crohn’s disease, on the other hand, did not cluster with either group.

In the future, the team hopes that the findings contribute not only to a better understanding of the biological pathways involved in these autoimmune diseases, but also give researchers a better sense of how to apply existing therapies — and come up with new ones.

“Several of these nine interesting SNPs we’ve found are located in or near genes that code for molecules found on cell surfaces,” Butte said, “which makes them potentially easier targets for the drugs pharmaceutical researchers are best at producing.”

And, Butte and his co-workers explained, the repertoire of SNPs involved will likely increase as additional autoimmune disease GWAS turn up new genetic variants involved in these — and other — diseases.

“As more genomic information becomes available on increasingly advanced platforms, this sort of analysis can be done on more diseases, possibly hundreds of them,” Sirota said.

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5 Comentários

Joyce Terzick said,

I was wondering about a gene connection between AS and CML. I was diagnosed with AS in 2000 and later Leukemia in 2006 and I have genetic changes from CML. I had enbrel and humira but don’t think they are linked. I would like to find someone that has both AS and CML to talk with and I was wondering if having the gene variations for AS are linked in the gene changes of CML. Thanks for your consideration of this question. If you are unable to answer this question could you direct me to someone who may be able to help me find out. Thanks!

rodrigobenevides said,

Sorry for taking to long to answer you.
Actually I don’t have an answer for you. Maybe you should get in contact with Mayo Clinic or MD Andeson Cancer Center. The have all sort of specialist that can provide you a beter understanding on this matter.

Anna said,

I find this study puzzling. I myself have been diagnosed with both Hashimoto’s Thyroiditis (age 12) and Ankylosing Spondylitis (age 21) with frequent bouts of iritis (12 occurrences since age 17). I was a participant in the AS genomic study which came out from the University of Texas Health Science Center. I don’t believe re-categorizing these autoimmune conditions to be relevant and in my case may have delayed diagnosis and thus treatment. I do believe more research is warranted to further investigate the possible relationships these specific genes may share in expressing such conditions. In a qualitative way I can say that while being treated with a biologic injectable for AS, neither my thyroid nor iritis conditions improved in any discernible way.

B said,

I have Ankylosing Spondylitis, Ulcerative Colitis and worst of all Multiple Sclerosis. I noticed that your findings suggest that someone with AS will be less likely to develop MS. Do you feel that a person with AS will not have MS? I was adopted and have both AS and MS in my biological family but that is all I know.

I would also like to know how all of these diseases work together. I don’t know what problem is from AS or MS.

I also have a daughter, 13 years old, and would like to know what is recommeded, if anything, to check for any genetic factors.

rodrigobenevides said,

Sorry for taking to long to answer you.
Actually I don’t have an answer for you. Maybe you should get in contact with Mayo Clinic or MD Andeson Cancer Center. The have all sort of specialist that can provide you a beter understanding on this matter.